Immune cells involved in cell-mediated inflammation (CMI) release arachidonic acid (AA) metabolites, cytokines, and reactive oxygen species (ROS) in response to skin irritants such as polycyclic hydrocarbons (PAHs). The resulting ROS and AA and cytokine cascades may set up a feedback loop that if maintained results in chronic inflammation. Chronic inflammation has long been known to be a risk factor for cancer. The tumor promoting PAH that will be used in these studies is a known skin irritant that result in skin hyperkeratinization and hyperplasia; early pathophysiological alterations occurring during the transformation to a tumorigenic phenotype. The working hypothesis is that topical applications of the prototypical PAH, TCDD, or TPA initiate a CMI and ROS feedback loop that modulates hyperkeratinization and hyperplasia induced by these compounds in mouse skin. The studies presented in this grant application are outlined below: Specific Aims 1 and 2 will determine the ability of TCDD, or TPA to initiate the release of AA and/or cytokines, and to generate ROS after topical application to the skin of hr/+ and hr/hr mice. These two Aims will establish the CMI and ROS portions of an inflammatory feedback loop. Specific Aim 3: By using specific inhibitors of key mediators in the CMI/ROS feedback loop, the contribution of AA metabolites, cytokines, and ROS in modulating the PAH-induced hyperkeratinization and hyperplasia will be determined. Specific Aim 4: To establish the relevancy of in vivo observations in the hr/hr and hr/+ mice to human exposures, from human keratinocytes will be cultured and treated in vitro with TCDD, or TPA.